Process for the manufacture of beta-hydroxy-steroid-ketones

ABSTRACT

A,B-OXIDO-STEROID-KETONES ARE CONVERTED INTO B-HYDROXYKETONES ACCORDING TO THE PARTIAL FORMULAE SCHEME   -C(=O)-(2,3-OXIRANYLENE)- --(H$/((ALK)SNH))--&gt; -C(=O)-   CH(-)-C(-CH)&lt;   WHEN THEY ARE TREATED WITH TRI-N-BUTYLSTANNANE IN AN ORGANIC SOLVENT WHILE IRRADIATING WITH ULTRAVIOLET LIGHT. NEW TYPES OF B-HYDROXY-STEROID-KETONES ARE INTER ALIA 17-OXYGENATED-7-METHYL-5-HYDROXY-3-OXO-ANDROSTANES AND 19NOR-ANDROSTANES, ESPECIALLY THE 7A-METHYL-DERIVATIVES AND CORRESPONDING $1-STEROIDS WITHOUT THE 7-METHYL GROUP.

United States Patent 3,565,778 PROCESS FOR THE MANUFACTURE OF B-HYDROXY-STEROID-KETONES Oskar Jeger, Zollikerberg, Zurich, Hans Ueli Wehrli, Schaifhausen, and Kurt Schalfner, Zurich, Switzerland, assignors to Ciba Corporation, New York, N.Y., a corporation of Delaware N0 Drawing. Filed July 9, 1968, Ser. No. 743,278 Claims priority, application Switzerland, July 13, 1967,

Int. Cl. B013 1/10 U.S. Cl. 204158 12 Claims ABSTRACT OF THE DISCLOSURE a,B-Oxido-steroid-ketones are converted into fl-hydroxyketones according to the partial formulae scheme when they are treated with tri-n-butylstannane in an organic solvent while irradiating with ultraviolet light. New types of fl-hydroxy-steroid-ketones are inter alia 17-oxygenated 7 methyl-5-hydroxy-3-oxo-androstanes and 19- nor-androstanes, especially the 7u-rnethyl-derivatives and corresponding A -steroids without the 7-methyl group.

BACKGROUND OF THE INVENTION There are already known p-hydroxy-steroid-ketones of the various steroid series with the functional groups in various positions of the cyclopentano-polyhydrophenanthrene or in the side chains, for example, in the pregnanc- 17fi side chain. Thus, inter alia in German specification No. 960,200, A -l6-hydroxy-3,20-diones, containing a free or esterified 2l-hydroxyl groups have been described. These compounds are pharmacologically active and act as suprarenal hormones. French Pat. 1,463,849 discloses 5-hydroxy-3-oxosteroids of the androstane and pregnanc series which are suitable for use as starting materials for the process, claimed in that French specification, for the manufacture of 5,10-secosteroids. l-hydroxy-B-oxosteroids of the pregnane series, especially the lot-hydroxy derivative of cortisone which has a much higher anti-inflammatory effect than cortisone, have been mentioned for instance in Japanese Pat. 22,142, and la-hydroxy-derivatives of the 5a-androstane series having a gOOd anabolicandrogenic activity in South African Pat. 63/ 5,165, and analogous compounds of the 5B-androstane series, which likewise have a good anabolic-androgenic activity, in Dutch patent application No. 6,501,292/ 65. The known methods for the manufacture of such hydroxy-steroidketones vary from case to case; thus, the pregnane compounds described in the aforementioned German patent are obtained by adding an arylcarbinol on to the 16,17- double bond of 16,17-unsaturated pregnanes and reductive splitting of the 16-aryloxy group formed. In the case of the above-mentioned French patent 4,5-oxido-3-ketones are temporarily ketalized and then reduced to S-hydroxy compounds with a complex light metal hydride. The lhydroxy-3-oxo-androstane compounds of the said South African patent are likewise obtained by splitting an oxido- 3-ketone, namely the epoxide group of a 1,2-oxido-3- ketone, but in this case the reduction is carried out with an alkali or alkaline earth metal in liquid ammonia or in an amine.

SUMMARY OF THE INVENTION The invention provides a new general method for the manufacture of p-hydroxy-steroids which consists in treat- Patented Feb. 23, 1971 ice DESCRIPTION OF THE PREFERRED EMBODIMENTS In the hydroxy-steroid-ketones obtainable with the new process of the invention the ketone group may be in the steroid ring system or in a side chain, and any desired configuration is possible at the various carbon atoms, especially also at those to which the hydroxyl group is attached. In this context the term steroid-ketones refers to any desired derivative of the cyclopentano-polyhydrophenanthrenes, that is to say not only to the normal steroids but, for example, also to 18- and 19-nor-steroids, A-homo-, B-homo-, A-nor-, B-nor-, C-noror D-homosteroids.

The steroid starting material used in the new process may be any ot,fi-oxido-steroid-ketone, for example of the androstane, pregnane, cholane, cholestane, spirostane, cardanolide or furostane series, for instance 4,5-oxido-3- oxo steroids, 1,2 oxido-3-oxo-steroids, 4,5-oxido-6-oxosteroids, 5,6 oxido-7-oxo-steroids, 9,1l-oxido-12-oxo-steroids, 9,10-oxido-ll-oxo-steroids or 3,4-oxido-2-oxo-steroids, which may contain in other free positions of the oxo-steroids, 4,5-oxido-6-oxo-steroids, 5,6-oxido-7-oxo-steroids, 9,11 oxido l2-oxo-steroids, 9,10-oxido-ll-oxo-steroids or 3,4-oxido-2-oxo-steroids, which may contain in other free positions of the steroid skeleton further substituents, and in the rings and/or possibly in the side chains, they may contain double bonds.

The starting materials are known or can be manufactured in known manner. For example, oz,fl-OXidO-ster0idketones are preferably manufactured by expoxidation of the corresponding unsaturated ketones by treatment with hydrogen peroxied in the presence of sodium hydroxide solution or by means of an organic peracid, such as perphthalic or perbenzoic acid.

The treatment according to this invention with a trialkylstannane with irradiation is carried out in an inert solvent that is stable towards the trialkylstannane and towards the ultraviolet light used for the irradiation, if desired or required with addition of a sensitizer.

Preferred solvents are aliphatic, cycloaliphatic or aromatic hydrocarbons, especially benzene.

As sensitizers there may be used those which are generally employed in photoinduced reactions, for example ,triphenylene.

A suitable source of light for the irradiation according to this invention is artificial or natural ultraviolet light, preferably ultraviolet light as emitted by mercury highpressure burners. The irradiation is preferably performed at room temperature.

Preferred trialkylstannanes are tri-lower alkylstannanes, above all tri-n-butylstannane.

Some of the process products are known and, as mentioned above, they may be used as intermediates in the manufacture of pharmacologically active compounds or they possess as such pharmacological properties.

The present invention further includes new fl-hydroxysteroid-ketones, in fact 17-oxygenated 7 -methyl-5-hydroxy- 3-oxo-androstanes and l9-nor-androstanes, especially 7ozmethyl derivatives of this type; also 17-oxygenated A -5- hydroxy-3-oxo-androstenes and 19-nor-androstenes, especially also their 7-rnethyl derivatives; and l7-oxygenated 5fl-hydroxy-3-oxo-l9-nor-androstanes.

This group of new compounds are thus 17-oxygenated -hydroxy-3-oxo-compounds of the 50cand Sfl-androstane and 19-nor-androstane series, which compounds are characterized by the presence of at least one of the following features: the 1,2-double bond, at 7-methyl group, or the [St-configuration at C5 together with the 19-nor-structure.

In these compounds the substituent in position 17 is, for example, either an oxo group or a free, etherified or esterified hydroxyl group together with a hydrogen atom or with an unsubstituted or substituted, saturated or unsaturated lower aliphatic hydrocarbon residue.

An esterified hydroxyl group is above all one derived from an organic carboxylic acid of the aliphatic, alicyclic, aromatic or heterocyclic series, especially one that contains 1 to 18 carbon atoms, for example formic, acetic, propionic acid, a butyric acid, a valeric such as n-valeric acid, or trimethylacetic, trifluoroacetic acid, a caproic acid such as fl-trimethylpropionic acid or diethylacetic acid, oenanthic, caprylic, pelargonic, capric acid and undecyclic acid, for example, undecylenic acid, lauric, myristic, palmitic or stearic acids, for example oleic acid, cyclopropane-, cyclopentane-, and cyclohexane-carboxylic acid, cyclopropylmethanecarboxylic, cyclobutylmethanecarboxylic, cyclopentylethanecarboxylic, cyclohexylethanecarboxylic acid, cyclopentylcyclohexylor phenyl-acetic or -propionic acids, benzoic, phenoxyalkanoic acids such as phenoxyacetic acid, dicarboxylic acids such as succinic acid, phthalic, quinolic acid, furan-Z-carboxylic, S-tertiary butyl-furan-2-carboxylic, 5-bromofuran-2-carboxylic acid,

nicotinic or isonicotinic acid, or from an inorganic acid,

for example a phosphoric or sulphuric acid.

An etherified hydroxyl group is especially one derived from an alkanol with 1 to 8 carbon atoms, such as a lower aliphatic alkanol, such as ethanol, methanol, propanol, isopropanol, butyl or amyl alcohol, or from an araliphatic alcohol, especially from a monocyclic aryllower aliphatic alcohols such as benzyl alcohol, or from a heterocyclic alcohol such as a-tetrahydropyranol orfuranol.

The lower aliphatic hydrocarbon residue in position 170a may be saturated or unsaturated, unsubstituted, or substituted, for example, by halogen atoms. Preferably, such a residue contains 1 to 4 carbon atoms and is in the first place methyl, ethyl, propyl, vinyl, allyl, methallyl, ethinyl, propinyl, trifluoropropinyl or trichloropropinyl.

Specific compounds in these new groups are, for example, 7a-methyl-5B, 17fl-dihydroxy-androstan-3-one and 70: methyl-5B,17/3-dihydroxy-l9-nor-androstan-3-one and their esters, for example their 17-monoesters or 55,175- diesters, for example the 17-acetates, 7a,17ot-dimethyl- 5,8, 17fi-dihydroxy-androstan-3-one and 7a-l7u-dimethyl- 55,17fi-dihydroxy-19-nor-androstan-3-one and their esters, for example their 518,17B-diesters; also A -5fi,17,8-dihydroxy-androsten-3-one and A -5/5',17,8-dihydroxy-l9-norandrosten-3-one and their esters, for example the 17- acetates; 17a-methy1-5B,17B-dihydroxy-19-nor-androstan- 3-one and 17a-ethinyl-5fl,17B-dihydroxy-19-nor-androstan- 3-one.

Another group of the new compounds of the present invention includes the 17-oxygenated A -1u-hydroxy-3- oxo-androstenand -19-nor-androstenes. The 17-oxygenated residue in position 17 is one of the groups defined above, the ester and ether groups and a lower aliphatic hydrocarbon residue in position 17a preferably likewise being those mentioned above. Special mention deserve, for example, A -1u,17/3-dihydroxy-androsten-3-one and its esters, for example 17,8-monoesters or 1,17,8-diester, especially the 17-acetate.

The new compounds of the present invention and especially the compounds specifically mentioned above are distinguished by their high androgenic and anabolic or an antiandrogenic activity.

Another object of the present invention are the starting materials to be used in the present process for the manufacture of the new A -1u-hydroxy-andr0stenand -19-norandrostenes said above, thus the 17-oxygenated A -1oz,2oc oxido-3-oxo-androstene and -19-nor-androstene compounds, for example A -1u,2a-oxido-l7fi-hydroxy-androsten-3-one and its esters, such as the 17-acetate, and A 1ot,2 z-oxido-17B-hydroxy-l9-nor-androsten-3-one and its 17-esters, such as the 17fl-acetate.

The invention includes also any variant of the process in which an intermediate obtained at any stage is used as starting material and any remaining step/steps is/ are carried out, or the process is discontinued at any stage thereof, or in which a starting material is formed under the reaction conditions.

The invention includes also the manufacture of pharmaceutical preparations for use in human or veterinary medicine, which contain the new pharmacologically active substances of the present invention described above as active ingredients, in conjunction or admixture with a pharmaceutical excipient. The excipient used may be an organic or inorganic substance suitable for enteral, for example oral, parenteral or local administration. Suitable excipients are substances that do not react with the new compounds, for example water, gelatin, lactose, starches, magnesium stearate, talcum, vegetable oils, benzyl alcohols, gums, polyalkyleneglycols, white petroleum jelly, cholesterol or other known medicinal excipients. The pharmaceutical preparations may be in solid form, for example tablets, dragees or capsules, or in liquid or semiliquid form solutions, suspensions, emulsions, ointments or creams. These pharmaceutical preparations may be sterilized and/or contain assistants such as preserving, stabilizing, wetting or emulsifying agents, salts for regulating the osmotic pressure or bulfers. They may also contain further therapeutically valuable substances. The new compounds may also be used as starting materials in the manufacture of other valuable compounds.

The products of the present invention may also be used as additives to animal fodders.

The following examples illustrate the invention.

Unless otherwise indicated, the irradiation is performed in benzene in a quartz test tube with a mercury highpressure burner. The infrared spectra and optical rotations have been measured in chloroform and the ultraviolet spectra in ethanol. The irradiated products have been purified by three recrystallizations from acetone-l-petroleum ether in each case.

EXAMPLE 1 mg. of 45,5,8-oxido-17fi-acetoxy-androstan-3-one are mixed with 2 ml. of tri-n-butylstannane and 8 ml. of benzene and the mixture is irradiated for half an hour. The resulting reaction solution is then immediately chromatographed on silica gel, the excess stannane and its reaction products being eluted with benzene. A 4:1- mixture of benzene-l-ethyl acetate then furnishes 12 mg. of unreacted starting material. The later benzene-l-ethyl acetate lzl-fractions furnish 74 mg. of 5,8-hydroxy-17fl-acetoxy-androstan-3-one melting at 176 to 178 C. (after 3 recrystallizations). Optical rotation [a] =]27 (0.37). Infrared spectrum: bands at 1028, 1255, 1712 (broad) and 3600 cmf EXAMPLE 2 100 mg. of 4/3,5fl-oxido-7a,17u-dimethyl-17B-hydroxy- 19-nor-androstan-3-one are treated and worked up as described in Example 1.

There are obtained 54 mg. of 7a,l7a-dimethyl-5,B,17fidihydroxy-l9-nor-androstan-3-one, melting at 206 to 208 C. Optical rotation [u] 1 1 (0.50). Infrared spectrum: bands at 1712 and 3595 cmr In addition 31 mg. of starting material are recovered.

EXAMPLE 3 100 mg. of 4,8,5B-oxido-l7ot-methyl-17B-hydroxy-19- norFandrostan-3-one are treated as described in Example 1, to yield 71 mg. of 17a-methyl-5,B,l7fi-dihydroxy-l9-norandrostan-3-one, melting at 181 to 183 C. Optical rotation [a] =+7 (0.40). Infrared spectrum: bands at 1711 and 3595 cmf 24 mg. of starting material are recovered.

EXAMPLE 4 100 mg. of A -3/3-acetoxy-16a,17u-0xido-pregnen-20- one are treated as described in Example 1 (irradiation time: 2 /2 hours), to yield 23 mg. of A -3fl-acetoxy-pregnene-16,20dione and 27 mg. of A -3B-acetoxy-16a-hydroxy-pregnen-ZO-one, melting at 168 C. Optical rotation [a] =7.5 (0.4). Infrared spectrum: bands at 1256, 1703, 1730 and 3605 cmf 30 mg. of starting material are recovered.

EXAMPLE 5 100 mg. of 1a,2 x-oxido-17,8-acetoxy-5a-androstan-3- one are treated as described in Example 1, to yield, inter alia, 44 mg. of 17fl-acetoxy-5a-androstan-3-one (identified by mixed melting point, infrared spectrum and thin-layer chromatogram) and 39 mg. of loc-l'lYdIOXY-l7fi-3CC1OXY- 5u-androstan-3-one, melting at 239 to 243 C. Optical rotation [a] =+20 (0.46). Infrared spectrum: bands at 1250, 1720 and 3600 cmf EXAMPLE 6 A mixture of 100 mg. of A 1a,2a-oxido-17fl-acetoxyandrosten-3-one and 1 ml. of tri-n-butyl-stannane in 5 ml. of dioxane is irradiated for 3 /2 hours with a mercury lowpressure burner, then evaporated under vacuum and chromatographed on silica gel, to yield inter alia 27 mg. of A 1 hydroxy methylene 17 6 acetoxy A nor androsten-2-one (identified by mixed melting point, infrared spectrum and thin-layer chromatogram) and 31 mg. of A 1a hydroxy-17fl-acetoxyandrosten-3-one, melting at 229 to 231 C. Optical rotation [a] =+73 (0.45). Infrared spectrum: 1255, 1620, 1670, 1730, 3600 cmf Ultraviolet spectrum: :243 m (e=15200). 18 mg. of starting material are recovered.

EXAMPLE 7 200 mg. of A -4fl,5/3-oxido-17B-acetoxy-androsten-3- one are treated and worked up as described in Example 6. After chromatography on silica gel in benZene-i-ethyl acetate mixtures there are obtained:

(a) 50 mg. of 45,5,6-oxido-l7fl-acetoxyeandrostan-3-one.

(b) 19 mg. of A -17,8-acetoxy-5,IO-seco-androstene- 3,5-dione; M.P. 215 C.; optical rotation [eth l-331 infrared spectrum: 1254 and 1720 (broad) cm.- ultraviolet spectrum:

x 290 m v (e=2300, in ethanol) A 302 my (e=20300 in alcoholic 0.1 N-KOH) 6 (c) 13.5 mg. of testosterone acetate. (d) 32 mg. of O-acetyl-l-dehydrotestosterone. (e) 33 mg. of 5,6-hydroxy-17fl-acetoxy-androstan-3-one. (f) 54 mg. of A -5fi-hydroxy-17/3-acetoxy-androsten-3- one. M.P. 172 C.; optical rotation [a] =+86 (0.28);

infrared spectrum: 1028, 1253, 1678, 1728, 3590 cm.- ultraviolet spectrum: M :232 m (6 9600).

EXAMPLE 8 mg. of 4a,5a-oxido-17B-acetoxy-androstan-3-one are treated as described in Example 1, to yield, inter alia, 59 mg. of 17B-acetoxy-5a-androstan-3-one and 82 mg. of a crystalline lzl-mixture of 5 B-hydroxy-17B-acetoxy-androstan-3-one and 5a-hydroxy-17B-acetoxy-androstan-3-one.

We claim:

1. Process for the manufacture of fi-hydroxy-steroidketones, wherein an a,B-oxido-steroid-ketone is treated with a trialkylstannane in an inert solvent while being irradiated with ultraviolet light.

2. Process according to claim 1, wherein irradiation is performed at room temperature.

3. Process according to claim 1, wherein ultraviolet light as emitted by mercury high-pressure burners is used.

4. Process according to claim 1, wherein the trialkyl stannane used is tri-n-butyl-stannane.

5. Process according to claim 1, wherein the irradiation is performed in a member selected from the group consisting of a saturated aliphatic and cycloaliphatic hydrocarbon.

6. Process according to claim 1, wherein the irradiation is performed in an aromatic hydrocarbon.

7. Process according to claim 1, wherein the irradiation is performed in benzene.

8. Process according to claim 1, wherein the irradiation is performed in the presence of a sensitizer.

9. Process according to claim 1, wherein the irradiation is performed in the presence of triphenylene as a sensitizer.

10. Process according to claim 1, wherein a 4,5-oxido- 3-oxo-steriod is used as starting material.

11. Process according to claim 1, wherein a 1,2-oxido- 3-oxo-steroid is used as starting material.

12. Process according to claim 1, wherein a 9,11-oxido- 12-oxo-steroid is used as starting material.

References Cited UNITED STATES PATENTS 3,494,843 2/1970 Jeger et al 204- 158 HOWARD S. WILLIAMS, Primary Examiner 

